Apparatus and method for coating implantable devices

ABSTRACT

A coating for implantable devices, such as stents, and a method of making the same is disclosed. Moreover, an apparatus for depositing the coating is disclosed.

CROSS REFERENCE TO RELATED APPLICATION

This is a divisional application of U.S. Ser. No. 09/997,390, which wasfiled on Nov. 30, 2001.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates generally to implantable devices, such as stents.More particularly, the present invention relates to an apparatus andmethod for coating stents.

2. Description of the Background

Implanting a stent, after a percutaneous transluminal coronaryangioplasty (PTCA) procedure, is often used to avoid or mitigate theeffects of restenosis at a surgical site. In general, stents are small,cylindrical devices whose structure serves to create or maintain anunobstructed opening within a lumen. Stents are typically made of, forexample, stainless steel, Nitinol or other materials and are deliveredto the target site via a balloon catheter. Although the stents areeffective in opening the stenotic lumen, the foreign material andstructure of the stents themselves may exacerbate the occurrence ofrestenosis or thrombosis.

In addition to using a stent, drugs or therapeutic agents that limitmigration and/or proliferation of vascular smooth muscle cells are usedto significantly reduce the incidence of restenosis and thrombosis.Examples of therapeutic agents commonly used include heparin, aspirin,IIb/IIIa inhibitors, antithrombogenic agents, dexamethasone, steroids,antiinflammatory agents, cytostatic agents, cytotoxic agents,antimicrobials, thrombolytics, monoclonal antibodies, tranilast, andantifibrosis agents. Since the therapeutic agents are appliedsystemically to the patient, they are absorbed not only by the tissuesat the target site, but by other areas of the body. As such, onedrawback associated with the systemic application of drugs is that areasof the body not needing treatment are also affected. To provide moresite-specific treatment, stents are frequently used as a means ofdelivering drugs exclusively to the target site. Drugs are suspended intissue-compatible polymers such as silicones, polyurethanes, polyvinylalcohol, poly(ethylene-co-vinyl alcohol), polyethylene, hydrogels,substituted methacrylates, poly(ethylene-co-vinyl acetate), andhyaluronic acid and blended mixtures thereof. By positioning the stentat the target site, the drugs can be applied directly to the area of thelumen requiring therapy.

Although stents with a drug coating have been an advance for thetreatment of restenosis and other similar vascular ailments, the stents,and the methods and apparatus for their production have not yet beenperfected. For instance, conventional techniques often apply a singlecoating of a homogenous composition that contains a mixture of a polymerand a therapeutic substance. The use of a homogenous composition mayhave several flaws. The polymeric portion of the coating may not bestable in the vascular environment (i.e., the polymer may leach into theblood), and may not be capable of holding a sufficient amount of thedrug. In addition, conventional coatings may not have a blood compatiblesurface to the vascular environment. Moreover, the drug release rate ofa coating made from a homogenous composition cannot be tailored toprovide for different release profiles.

As an alternative to using a homogenous composition to coat a stent,some conventional techniques apply a coating to a stent that has morethan one layer, with each layer having a different composition. Thesetechniques also suffer from some flaws. For example, the differentlayers may not strongly adhere to each, thereby allowing one or morelayer to leach into the blood or become detached creating anembolization hazard. Also, the coating process of these techniques maynot be very efficient because each layer must be applied, and then driedbefore the next layer is applied. Finally, the application of thecomposition for each additional layer subsequent to the drying of thepreviously applied layer can cause the extraction of the drug out of theprevious layer. Accordingly, the concentration of the drug will residein the upper most layers, causing a rapid release of the drug subsequentto the implantation procedure. This “burst-effect” leads to a reducedresidence time of the drug at the implantation site, which may beundesirable depending on the type of condition being treated.

Accordingly, what is needed is an apparatus and process for coatingstents that does not suffer from the aforementioned drawbacks. Moreparticularly, there is a need for a method and apparatus for coating astent that is able to modify the coating formulation as the formulationis being applied to the stent.

SUMMARY OF THE INVENTION

The present invention is directed to a method of forming a coating on animplantable device such as a stent including applying a coatingformulation to a stent, the coating formulation including a firstingredient and a second ingredient, and modifying the ratio of the firstingredient with respect to the second ingredient in the coatingformulation as the coating formulation is being applied to the stent. Inone embodiment, the act of applying includes spraying the coatingformulation on the stent.

The present invention is further directed to a system for applying acoating on a stent, including a nozzle for spraying a composition onto astent, a first reservoir in fluid communication with the nozzle forsupplying a first ingredient of the composition to the nozzle, a secondreservoir in fluid communication with the nozzle for supplying a secondingredient of the composition to the nozzle, and a control assembly foradjusting the amount of the first or second ingredient that is fed intothe nozzle wherein the amount of the first or second ingredient that issprayed by the nozzle can be modified by the control assembly withoutinterrupting the application of the composition onto the stent. Thesystem may further have a mixer for mixing the first ingredient with thesecond ingredient. In one embodiment, the control assembly includes avalve for adjusting the input rate of the first or second ingredient tothe nozzle.

The present invention is also directed to an implantable medical devicehaving a coating having a first ingredient and a second ingredient,wherein from a deep region of the coating to a more shallow region ofthe coating, the ratio of the concentration of the first ingredient tothe concentration of the second ingredient gradually increases ordecreases.

In the embodiments of the present invention, the ingredients can be apolymeric material and a therapeutic substance. Some examples ofpolymeric materials can include ethylene vinyl alcohol copolymer,polybutylmethacrylate, polyethylene glycol, amorphous Teflon, andpoly(ethylene-co-vinyl acetate). Some examples of therapeutic substancescan include actinomycin D, paclitaxel, docetaxel, rapamycin, β-estradioland BAK Heparin.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates a coating system for forming a coating on a stent;

FIG. 2 illustrates a coating system for forming a coating on a stent;

FIG. 3 is a graph showing the relative concentration of two ingredientsas a function of application time;

FIGS. 4 and 5 are graphs, in accordance with two embodiments, showingthe concentration of two ingredients as a function of application timeand thickness of the coating;

FIGS. 6 and 7 are graphs, in accordance with other embodiments, showingthe concentration of three ingredients as a function of application timeand thickness of the coating;

FIG. 8 is a diagram of an embodiment of an implantable medical deviceinserted into a body vessel; and

FIG. 9 illustrates a partial cross-section of a strut, in accordancewith one exemplary embodiment, along the line 9-9 of FIG. 8.

DETAILED DESCRIPTION OF THE EMBODIMENTS System for Coating

An embodiment of the present invention involving a system for spraycoating an implatable device such as a stent is depicted in FIG. 1.Although a spray system is depicted in the spirit of convenience andbrevity, it should be noted that other systems and methods are alsowithin the scope of the claimed invention.

Referring to FIG. 1, a gas source such as an air compressor 10 mayprovide air pressure to a first reservoir 16 and a second reservoir 20through a first air hose 12 and a second air hose 14, respectively.First reservoir 16 can hold a first solution 18 which includes a firstingredient (e.g., a polymeric material) and a solvent. Second reservoir20 can hold a second solution 22 which includes a second ingredient(e.g., a therapeutic substance) and a solvent. It is understood that anynumber of reservoirs can be used to contain any number of ingredients.The air pressure delivered from air compressor 10 can be sufficientlyhigh enough to promote uptake of the solutions in first reservoir 16 andsecond reservoir 20 into a first fluid hose 24 and a second fluid hose26. First solution 18 and second solution 22, in turn, can be fed into acontrol assembly 34, which controls the rate that compositions fromfirst reservoir 16 and second reservoir 20 are delivered to a mixer 32.

First solution 18 and second solution 22 are mixed in mixer 32, and thenmoved as a mixed solution to a nozzle 42. As the mixed solution entersthe chamber of nozzle 42, the mixed solution is exposed to pressurizedair from two sources: an actuating gas source 38 and an atomizing gassource 40. Atomizing gas source 40, which can deliver air or anothergas, provides sufficient pressure and velocity to atomize the solutioninto small droplets. Actuating gas source 38, on the other hand, canprovide a sufficient amount of pressure so that the droplets are forcedout of nozzle 42 and directed to a target (e.g., a stent).

As noted above, control assembly 34 can monitor and control the rate offluid delivered to mixer 32 and nozzle 42. Control assembly 34 can havea controller 36 (e.g., a CPU) that is in communication with a firstvalve 28 and a second valve 30. First valve 28 and second valve 30 maybe, for example, high precision proportioning valves as is well knownand commonly available to those of ordinary skill in the art.Alternatively, first valve 28 and second valve 30 could be very lowvolume, high speed valves (Lee Electro-Fluidic Systems, Westbrook,Conn.).

In another embodiment, referring to FIG. 2, a first reservoir 54 and asecond reservoir 56 are in fluid communication with nozzle 42 fordelivering two different ingredients to nozzle 42. Instead of a gassource such as air compressor 10, a first syringe pump 50 and a secondsyringe pump 52 may provide pressure to first reservoir 54 and secondreservoir 56, respectively. Syringe pumps 50 and 52, in turn, are incommunication with controller 36. Controller 36 may provide signals tosyringe pumps 50 and 52 and control the amount of motive force thatsyringe pumps 50 and 52 provide to reservoirs 54 and 56, therebycontrolling the amount of ingredients that are ultimately delivered tonozzle 42.

Various approaches may be used to mix the ingredients delivered by thereservoirs. In one embodiment, referring to FIG. 1, the ingredients aremixed in mixer 32 before they are delivered to nozzle 42. Representativeexamples of types of mixers that can be employed include an ultrasonicmixer having a piezoelectric transducer, a static mixer and a mechanicalmixer. Alternatively, the ingredients can be mixed as the ingredientsare introduced into and/or ejected out from nozzle 42.

Various structures can be used to support the stents while they arebeing sprayed by nozzle 42. By way of example, and not limitation, astent 44 (FIG. 1) can be attached to a mandrel 46 that rotates and/ormoves in a linear direction during the application process.Alternatively, nozzle 42 can pivotly rotate around and move linearlyalong a stationary stent.

Method of Applying Coating

In one embodiment of the present invention, a method is used to apply acoating formulation to a stent, whereby the coating formulation has atleast two ingredients and the relative concentrations of the ingredientsare modified as the coating formulation is applied to the stent. In oneembodiment, the coating formulation is applied to the stent by spraying.Referring to FIG. 1, first solution 18 can contain a first ingredient(e.g., a polymeric material), and second solution 22 can contain asecond ingredient (e.g., a therapeutic substance). A gas source such asair compressor 10 can provide the motive force to deliver first solution18 and second solution 22 to first valve 28 and second valve 30,respectively. Control assembly 34 can be used to control the amount offirst solution 18 and second solution 22 that is delivered to mixer 32,and ultimately the amount delivered to nozzle 42. For example, whilenozzle 42 is spraying a stent, controller 36 can modify the ratio offirst solution 18 with respect to second solution 22 by controlling theoperation of first and second valve 28 and 30.

In one embodiment, for example, first solution 18 contains ingredient A(a therapeutic substance), and second solution 22 contains ingredient B(a polymeric material). While nozzle 42 is spraying stent 44, controller36 can send signals to first valve 28 to reduce the flow rate of firstsolution 18. As a result, the amount of first solution 18, and thereforeingredient A, that is delivered to mixer 32 is reduced, therebymodifying the contents of the composition of the coating formation thatis sprayed onto stent 44. In addition, while nozzle 42 is spraying stent44, controller 36 can send signals to second valve 30 to increase theflow rate of second solution 22. For example, as shown in FIG. 3, at theearly segments of the application process, the concentration ofingredient A relative to the concentration of ingredient B issignificantly higher. However, as the application process proceeds, theconcentration of ingredient B can be incrementally increased while theconcentration of ingredient A is concurrently decreased relative to theconcentration of ingredient B.

In another embodiment, the coating formulation contains ingredient C andingredient D. Referring to FIG. 4, the concentration of ingredient C canremain constant as the coating is applied, while the concentration ofingredient D remains constant for an initial period, then increases, andthen becomes constant at a later stage of the application.

In a yet another embodiment, the coating formulation can containingredient E and ingredient F. Referring to FIG. 5, ingredient E canfirst be applied as a primer, and then ingredient F can be graduallymixed with ingredient E at an increasing concentration.

In one exemplary implementation of the ingredients of FIG. 5, ingredientE can be ethylene vinyl alcohol copolymer (EVAL), and ingredient F canbe polyethylene glycol (PEG). EVAL is considered to have relatively goodadhesion potential, whereas PEG is considered to have relatively highblood compatibility. A single coating with a large fraction of PEGrelative to EVAL would likely give high blood compatibility but wouldswell significantly, perhaps dissolving off of the stent, releasing PEGinto the blood, and generally not adhering well to the stent. Aformulation with a high percentage of EVAL, in turn, would likely adhereto the stent surface, but would not be as blood compatible as PEG. Inorder to realize the benefits of combining EVAL and PEG, one could applya coating formulation as shown in FIG. 5.

In another embodiment, the coating formulation contains ingredient G,ingredient H and ingredient I. By way of example and not limitation,ingredient G can be a therapeutic substance, ingredient H can be EVAL,and ingredient I can be poly(ethylene-co-vinyl acetate). Referring toFIG. 6, ingredient H can be first applied to the stent at constantconcentration as a primer. Then, ingredient G can be added with anincreasing concentration to provide a drug layer. About one-half the waythrough the application process, ingredient I is added to the coatingformulation. The concentration of ingredient I increases through therest of the coating process, while the concentration of ingredient Hdecreases. At the end of the coating process, with respect to ingredientG, ingredient H and ingredient I, the coating formulation only containsingredient I, thereby providing a topcoat layer.

In another embodiment, the coating formulation contains ingredient J,ingredient K and ingredient L. Referring to FIG. 7, ingredient J isinitially applied to a stent as a primer. However, as the applicationprocess continues, the concentration of ingredient J in the coatingformulation decreases. While ingredient J is being applied, ingredientsK and L are added to the coating formulation, and the concentrations ofingredient K and L increase throughout the remainder of the coatingapplication. For example, ingredient J is polybutylmethylmethacrylate(PBMA), ingredient K is EVAL and ingredient L is Actinomycin D, with thecommon solvent dimethylacetamide.

Implantable Device

A stent is broadly intended to include self-expandable stents,balloon-expandable stents, and stent-grafts. One of ordinary skill inthe art, however, understands that other medical devices on which apolymeric material can be coated can be used with the practice of thepresent invention, such as grafts (e.g., aortic grafts), artificialheart valves, cerebrospinal fluid shunts, axius coronary shunts,pacemaker electrodes, and endocardial leads (e.g., FINELINE and ENDOTAK,available from Guidant Corporation). The underlying structure of thedevice can be of virtually any design. The device can be made of ametallic material or an alloy such as, but not limited to, cobaltchromium alloy (e.g., ELGILOY), stainless steel (316L), “MP35N,”“MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,platinum-iridium alloy, gold, magnesium, or combinations thereof.“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from standard Press Steel Co.,Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. Devices made frombioabsorbable or biostable polymers could also be used with theembodiments of the present invention.

FIG. 8 illustrates an implantable prosthetic medical device. In thespirit of convenience and brevity, the medical device referenced in thetext and figures of the present disclosure is a stent 60. Stent 60 canbe cylindrical or tubular in shape, and can be inserted into a bodylumen 62. The structure of stent 60 should allow stent 60 to be insertedinto and physically uphold an anatomical passageway such as body lumen62, by exerting a radially outward-extending force against the walls orinner lumen surface of the passageway. If desired, stent 60 can alsoexpand the opening of lumen 62 to a diameter greater than its originaldiameter and, thereby, increase fluid flow through lumen 62.

Stent 60 can include struts 70 that form a network structure. Struts 70have an outer (or lumen contacting) surface 64 and an inner surface 66,as shown in FIG. 8. In addition, a hollow bore 68 extends longitudinallythrough the body structure of stent 60.

In one embodiment of the present invention, a coating formulation with afirst ingredient and a second ingredient is used to coat outer surface64 of struts 70, and the resultant coating has a first region and asecond region, where the quantity of the first ingredient with respectto the second ingredient is different in the first region as compared tothe second region. In another embodiment, the coating formulation hasthree or more different ingredients. In a further embodiment, thecoating has three or more different regions. Referring to FIG. 9, by wayof illustration, the coating of strut 70 has a first region 72, a secondregion 74, a third region 76, a fourth region 78, a fifth region 80 anda sixth region 82. In the interests of brevity and simplification, thedifferent regions are illustrated only on outer surface 64 of strut 70.However, one of ordinary skill in the art will understand that thecoating can also be on inner surface 66 of strut 70, as well as allother surfaces of stent 60.

Referring to FIG. 9, first region 72 may be used as a primer, and fifthregion 80 may used as a rate reduction membrane to reduce the releaserate of a therapeutic substance contained in second region 74, thirdregion 76, and fourth region 78. Sixth region 82 may be used as a bloodcompatible layer. Furthermore, by gradually changing the concentrationof the ingredients contained in the regions, there may be increasedinterlayer adhesion. For instance, second region 74, third region 76,fourth region 78, and fifth region 80 can be used for increasedinterlayer adhesion between first region 72 and sixth region 82. One ofordinary skill in the art will understand that fewer than six regions ormore than six regions may be applied as part of the present invention.

By way of example, the coating formulation may include ingredient M,ingredient N, ingredient O and ingredient P. Referring to Table I, forinstance, the concentrations of the various ingredients relative to eachother may be changed in the different regions. TABLE I ConcentrationRelative to Other Ingredients (%) Ingredient Region M Ingredient NIngredient O Ingredient P First Region 72 100 0 0 0 Second Region 74 6020 20 0 Third Region 76 30 30 30 10 Fourth Region 78 10 40 30 20 FifthRegion 80 0 50 25 25 Sixth Region 82 0 40 20 40

In yet another embodiment of the present invention, the coatingformulation includes ingredient Q, ingredient R, ingredient S andingredient T. Referring to Table II, for example, the concentrations ofthe various ingredients may be changed in the different regions. In oneexemplary implementation of the ingredients of Table II, ingredient Q isPBMA, ingredient R is EVAL, ingredient S is Actinomycin D, andingredient T is PEG (molecular weight 15,000 amu). TABLE IIConcentration (mg/ml) Ingredient Region Q Ingredient R Ingredient SIngredient T First Region 72 1100 0 0 0 Second Region 74 733 380 0 0Third Region 76 367 760 0 0 Fourth Region 78 0 1026 114 0 Fifth Region80 0 1140 0 0 Sixth Region 82 0 977 0 163

The pure PBMA in first region 72 can act as a primer and afford goodadhesion with the stent surface. Also, one disadvantage of the currentcoating processes is that there is poor interlayer compatibility amongsome components, such as polymeric materials. Certain polymericmaterials, for instance, do not properly adhere to each other when theyare applied in layers in their pure form. The graduated interfacebetween the PBMA and EVAL in regions 72, 74 and 76, as depictednumerically in Table II, may provide better interlayer adhesion.

In a further embodiment of the present invention, the coatingformulation includes ingredient U, ingredient V, ingredient W andingredient X. In one exemplary implementation of the ingredients ofTable III, ingredient U is PBMA, ingredient V is EVAL, ingredient W isβ-Estradiol, and ingredient X is the benzylalkonium salt of heparin (BAKHeparin). TABLE III Concentration (mg/ml) Ingredient Region U IngredientV Ingredient W Ingredient X First Region 72 0 1140 0 0 Second Region 740 760 380 0 Third Region 76 550 570 0 0 Fourth Region 78 1100 0 0 0Fifth Region 80 550 570 0 0 Sixth Region 82 0 1026 0 114

Composition of Coating Formulation

The ingredients contained in the coating formulation can be prepared byconventional methods. More particularly, in accordance to oneembodiment, a predetermined amount of a polymeric material orcombination of polymeric materials can be added to a predeterminedamount of a solvent or a combination of solvents. If necessary, heating,stirring and/or mixing can be employed to effect dissolution of thepolymeric material(s) into the solvent(s)—for example in an 80° C. waterbath for two hours.

A therapeutic substance can be also be an ingredient contained in thecoating formulation. In accordance to one embodiment, a predeterminedamount of a therapeutic substance or combination of therapeuticsubstances can be added to a predetermined amount of a solvent, acombination of solvents, with or without a polymeric material. Thetherapeutic substance should be in true solution or saturated in thecomposition of the coating formulation. If the therapeutic substance isnot completely soluble in the composition, operations including mixing,stirring, and/or agitation can be employed to effect homogeneity of theresidues. The therapeutic substance may be added so that dispersion isin fine particles. The mixing of the therapeutic substance can beconducted at ambient pressure and at room temperature.

Representative examples of polymeric material that can be used to coat amedical device in accordance with the present invention include ethylenevinyl alcohol copolymer (commonly known by the generic name EVOH or bythe trade name EVAL); polybutylmethacrylate; poly(hydroxyvalerate);poly(L-lactic acid); polycaprolactone; poly(lactide-co-glycolide);poly(hydroxybutyrate); poly(hydroxybutyrate-co-valerate); polydioxanone;polyorthoester; polyanhydride; poly(glycolic acid); poly(D,L-lacticacid); poly(glycolic acid-co-trimethylene carbonate); polyphosphoester;polyphosphoester urethane; poly(amino acids); cyanoacrylates;poly(trimethylene carbonate); poly(iminocarbonate); copoly(ether-esters)(e.g. PEO/PLA); polyalkylene oxalates; polyphosphazenes; biomolecules,such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronicacid; polyurethanes; silicones; polyesters; polyolefins; polyisobutyleneand ethylene-alphaolefin copolymers; acrylic polymers and copolymers;vinyl halide polymers and copolymers, such as polyvinyl chloride;polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidenehalides, such as polyvinylidene fluoride and polyvinylidene chloride;polyacrylonitrile; polyvinyl ketones; polyvinyl aromatics, such aspolystyrene; polyvinyl esters, such as polyvinyl acetate; copolymers ofvinyl monomers with each other and olefins, such as ethylene-methylmethacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins,and ethylene-vinyl acetate copolymers; polyamides, such as Nylon 66 andpolycaprolactam; alkyd resins; polycarbonates; polyoxymethylenes;polyimides; polyethers; epoxy resins; polyurethanes; rayon;rayon-triacetate; cellulose; cellulose acetate; cellulose butyrate;cellulose acetate butyrate; cellophane; cellulose nitrate; cellulosepropionate; cellulose ethers; amorphous Teflon; and carboxymethylcellulose. EVAL is functionally a very suitable choice of polymericmaterial. The copolymer possesses good adhesive qualities to the surfaceof a stent, particularly stainless steel surfaces, and has illustratedthe ability to expand with a stent without any significant detachment ofthe copolymer from the surface of the stent. The copolymer, moreover,allows for good control capabilities over the release rate of thetherapeutic substance.

Representative examples of solvents include chloroform, acetone, water(buffered saline), dimethylsulfoxide (DMSO), propylene glycol methylether (PM,) iso-propylalcohol (IPA), n-propylalcohol, methanol, ethanol,tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl acetamide(DMAC), benzene, toluene, xylene, hexane, cyclohexane, heptane, octane,nonane, decane, decalin, ethyl acetate, butyl acetate, isobutyl acetate,isopropyl acetate, butanol, diacetone alcohol, benzyl alcohol,2-butanone, cyclohexanone, dioxane, methylene chloride, carbontetrachloride, tetrachlroro ethylene, tetrachloro ethane, chlorobenzene,1,1,1-trichloroethane, formamide, pentane, trifluoroethanol,hexafluoroisopropanol, freon, hexamethylphosphorustriamide, andcombinations thereof.

The therapeutic substance can be for inhibiting the activity of vascularsmooth muscle cells. More specifically, the therapeutic substance can beaimed at inhibiting abnormal or inappropriate migration and/orproliferation of smooth muscle cells for the inhibition of restenosis.The therapeutic substance can also include any substance capable ofexerting a therapeutic or prophylactic effect in the practice of thepresent invention. For example, the therapeutic substance can be forenhancing wound healing in a vascular site or improving the structuraland elastic properties of the vascular site. Examples of therapeuticsubstances include antiproliferative substances such as actinomycin D,or derivatives and analogs thereof (manufactured by Sigma-Aldrich 1001West Saint Paul Avenue, Milwaukee, Wis. 53233; or COSMEGEN availablefrom Merck). Synonyms of actinomycin D include dactinomycin, actinomycinIV, actinomycin I₁, actinomycin X₁, and actinomycin C₁. The active agentcan also fall under the genus of antineoplastic, anti-inflammatory,antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic,antibiotic, antiallergic and antioxidant substances. Examples of suchantineoplastics and/or antimitotics include paclitaxel (e.g. TAXOL® byBristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g. Taxotere®,from Aventis S.A., Frankfurt, Germany) methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g.Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g.Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples ofsuch antiplatelets, anticoagulants, antifibrin, and antithrombinsinclude sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as Angiomax ä (Biogen, Inc., Cambridge, Mass.). Examplesof such cytostatic or antiproliferative agents include angiopeptin,angiotensin converting enzyme inhibitors such as captopril (e.g.Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.),cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co.,Inc., Whitehouse Station, N.J.); calcium channel blockers (such asnifedipine), colchicine, fibroblast growth factor (FGF) antagonists,fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (aninhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand nameMevacor® from Merck & Co., Inc., Whitehouse Station, N.J.), monoclonalantibodies (such as those specific for Platelet-Derived Growth Factor(PDGF) receptors), nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitors, suramin, serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), andnitric oxide. An example of an antiallergic agent is permirolastpotassium. Other therapeutic substances or agents which may beappropriate include alpha-interferon, genetically engineered epithelialcells, rapamycin and dexamethasone. Other therapeutic substances oragents which may be appropriate include alpha-interferon, geneticallyengineered epithelial cells, rapamycin and dexamethasone. The foregoingsubstances are listed by way of example and are not meant to belimiting. Other therapeutic substances which are currently available orthat may be developed in the future are equally applicable.

The dosage or concentration of the therapeutic substance required toproduce a favorable therapeutic effect should be less than the level atwhich the therapeutic substance produces toxic effects and greater thanthe level at which non-therapeutic results are obtained. The dosage orconcentration of the therapeutic substance required to inhibit thedesired cellular activity of the vascular region can depend upon factorssuch as the particular circumstances of the patient; the nature of thetrauma; the nature of the therapy desired; the time over which theingredient administered resides at the vascular site; and if othertherapeutic agents are employed, the nature and type of the substance orcombination of substances. Therapeutic effective dosages can bedetermined empirically, for example by infusing vessels from suitableanimal model systems and using immunohistochemical, fluorescent orelectron microscopy methods to detect the agent and its effects, or byconducting suitable in vitro studies. Standard pharmacological testprocedures to determine dosages are understood by one of ordinary skillin the art.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from theembodiments this invention in its broader aspects and, therefore, theappended claims are to encompass within their scope all such changes andmodifications as fall within the true spirit and scope of theembodiments this invention.

1. A system for applying a coating on a stent, comprising: a nozzle forspraying a composition onto a stent; a first reservoir in fluidcommunication with the nozzle for supplying a first ingredient of thecomposition to the nozzle; a second reservoir in fluid communicationwith the nozzle for supplying a second ingredient of the composition tothe nozzle; and a control assembly for adjusting the amount of the firstor second ingredient that is fed into the nozzle wherein the amount ofthe first and second ingredient that is sprayed by the nozzle can bemodified by the control assembly without interrupting the application ofthe composition onto the stent.
 2. The system of claim 1, furthercomprising a mixer for mixing the first ingredient with the secondingredient.
 3. The system of claim 1, wherein the first ingredient is apolymeric material and the second ingredient is a therapeutic substance.4. The system of claim 1, wherein the first ingredient is a firstpolymeric material and the second ingredient is a second polymericmaterial.
 5. The system of claim 1, wherein the control assemblyincludes a valve for adjusting the input rate of the first or secondingredient to the nozzle.
 6. An implantable medical device comprising acoating having a first ingredient and a second ingredient, wherein froma deep region of the coating to a more shallow region of the coating,the ratio of the concentration of the first ingredient to theconcentration of the second ingredient gradually increases or decreases.7. The implantable medical device of claim 6, wherein the firstingredient is a polymeric material and the second ingredient is atherapeutic substance.
 8. The implantable device of claim 7, wherein thepolymeric material is selected from the group consisting of ethylenevinyl alcohol copolymer, polybutylmethacrylate, polyethylene glycol,amorphous Teflon, and poly(ethylene-co-vinyl acetate).
 9. Theimplantable device of claim 7, wherein the therapeutic substance isselected from the group consisting of actinomycin D, paclitaxel,docetaxel, rapamycin, β-estradiol and BAK Heparin.
 10. The implantablemedical device of claim 6, wherein the first ingredient is a firstpolymeric material and the second ingredient is a second polymericmaterial.